Changes in the anticitrullinated peptide antibody response in relation to therapeutic outcome in early rheumatoid arthritis: results from the SWEFOT trial

Alf Kastbom, Kristina Forslind, Sofia Ernestam, Pierre Geborek, Johan A Karlsson, Ingemar F Petersson, Saedis Saevarsdottir, Lars Klareskog, Ronald F van Vollenhoven, Karin Lundberg, Alf Kastbom, Kristina Forslind, Sofia Ernestam, Pierre Geborek, Johan A Karlsson, Ingemar F Petersson, Saedis Saevarsdottir, Lars Klareskog, Ronald F van Vollenhoven, Karin Lundberg

Abstract

Objective: To determine the relationship between changes in antibody levels towards citrullinated peptides derived from different candidate autoantigens and therapeutic outcome in early rheumatoid arthritis (RA).

Methods: Baseline and 3-month serum samples from 316 patients with early RA enrolled in the Swedish Farmacotherapy (SWEFOT) trial were analysed for antibodies against cyclic citrullinated peptides (CCP) and citrullinated peptides derived from vimentin (cVim), fibrinogen (cFib) and α-enolase (CEP-1). At 3-month follow-up, methotrexate monotherapy-inadequate responders were randomised to add-on therapy with sulfasalazine and hydroxychloroquine or infliximab. In these patients, anticitrullinated peptide antibodies (ACPA) were also assessed at 12 and 24 months. The proportion of antibody-positive patients and relative changes in antibody levels were compared across ACPA specificities and related to therapeutic response and radiographic progression.

Results: During the 2-year follow-up, the proportion of patients testing positive declined significantly regarding antibodies to cVim, cFib and CEP-1, while anti-CCP antibody occurrence remained stable over time. Turning anti-cVim antibody negative was most common, and anti-cVim antibody seroreversion during the first three months associated with significantly less 2-year radiographic progression compared with patients who remained positive. Median antibody levels of all tested ACPAs declined uniformly during initial methotrexate therapy and following response to add-on therapy, with no significant relation to treatment regimen or radiographic progression.

Conclusions: The influence of early antirheumatic therapy on ACPA seroreversions was markedly different across specificities, and early disappearance of anti-cVim antibodies associated with better radiological outcome. Thus, these data suggest that the disappearance of particular ACPA reactivities may be beneficial in early RA.

Trial registration number: WHO database at the Karolinska institute: CT20080004; and clinicaltrials.gov: NCT00764725.

Keywords: Ant-CCP; Autoantibodies; DMARDs (biologic); DMARDs (synthetic); Early Rheumatoid Arthritis.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Figures

Figure 1
Figure 1
Relative change in levels of different anticitrullinated protein antibody (ACPA) specificities in patients with early rheumatoid arthritis receiving add-on therapy at 3 months. For each ACPA specificity, only patients testing positive at baseline were included. ***p

Figure 2

Status of different anticitrullinated protein…

Figure 2

Status of different anticitrullinated protein antibody specificities at different time points in early…

Figure 2
Status of different anticitrullinated protein antibody specificities at different time points in early rheumatoid arthritis. Only patients receiving add-on therapy were included (n=139). *p=0.019, **p=0.002, ***p

Figure 3

Relative changes in antibody levels…

Figure 3

Relative changes in antibody levels in relation to treatment response after 3 months…

Figure 3
Relative changes in antibody levels in relation to treatment response after 3 months of methotrexate therapy (A) and after 9 months of add-on therapy (B) in early rheumatoid arthritis. CCP, cyclic citrullinated peptide; CEP-1, citrullinated α-enolase peptide-1; cVim, citrullinated vimentin peptide; cFib, citrullinated fibrinogen peptide.

Figure 4

Relative changes in antibody levels…

Figure 4

Relative changes in antibody levels during months 3–12 in relation to add-on therapy…

Figure 4
Relative changes in antibody levels during months 3–12 in relation to add-on therapy regimen following inadequate response to methotrexate in early rheumatoid arthritis. CCP, cyclic citrullinated peptide; CEP-1, citrullinated α-enolase peptide-1; cVim, citrullinated vimentin peptide; cFib, citrullinated fibrinogen peptide; DMARD, disease-modifying anti-rheumatic drugs; TNF, tumour necrosis factor.
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    1. Willemze A, Trouw LA, Toes REM, et al. . The influence of ACPA status and characteristics on the course of RA. Nat Rev Rheumatol 2012;8:144–52. - PubMed
    1. Wegner N, Lundberg K, Kinloch A, et al. . Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol Rev 2010;233:34–54. - PubMed
    1. Snir O, Widhe M, von Spee C, et al. . Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles. Ann Rheum Dis 2009;68:736–43. - PubMed
    1. Goules JD, Goules AV, Tzioufas AG. Fine specificity of anti-citrullinated peptide antibodies discloses a heterogeneous antibody population in rheumatoid arthritis. Clin Exp Immunol 2013;174:10–7. - PMC - PubMed
    1. Lundberg K, Bengtsson C, Kharlamova N, et al. . Genetic and environmental determinants for disease risk in subsets of rheumatoid arthritis defined by the anticitrullinated protein/peptide antibody fine specificity profile. Ann Rheum Dis 2013;72:652–58. - PubMed
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Figure 2
Figure 2
Status of different anticitrullinated protein antibody specificities at different time points in early rheumatoid arthritis. Only patients receiving add-on therapy were included (n=139). *p=0.019, **p=0.002, ***p

Figure 3

Relative changes in antibody levels…

Figure 3

Relative changes in antibody levels in relation to treatment response after 3 months…

Figure 3
Relative changes in antibody levels in relation to treatment response after 3 months of methotrexate therapy (A) and after 9 months of add-on therapy (B) in early rheumatoid arthritis. CCP, cyclic citrullinated peptide; CEP-1, citrullinated α-enolase peptide-1; cVim, citrullinated vimentin peptide; cFib, citrullinated fibrinogen peptide.

Figure 4

Relative changes in antibody levels…

Figure 4

Relative changes in antibody levels during months 3–12 in relation to add-on therapy…

Figure 4
Relative changes in antibody levels during months 3–12 in relation to add-on therapy regimen following inadequate response to methotrexate in early rheumatoid arthritis. CCP, cyclic citrullinated peptide; CEP-1, citrullinated α-enolase peptide-1; cVim, citrullinated vimentin peptide; cFib, citrullinated fibrinogen peptide; DMARD, disease-modifying anti-rheumatic drugs; TNF, tumour necrosis factor.
Figure 3
Figure 3
Relative changes in antibody levels in relation to treatment response after 3 months of methotrexate therapy (A) and after 9 months of add-on therapy (B) in early rheumatoid arthritis. CCP, cyclic citrullinated peptide; CEP-1, citrullinated α-enolase peptide-1; cVim, citrullinated vimentin peptide; cFib, citrullinated fibrinogen peptide.
Figure 4
Figure 4
Relative changes in antibody levels during months 3–12 in relation to add-on therapy regimen following inadequate response to methotrexate in early rheumatoid arthritis. CCP, cyclic citrullinated peptide; CEP-1, citrullinated α-enolase peptide-1; cVim, citrullinated vimentin peptide; cFib, citrullinated fibrinogen peptide; DMARD, disease-modifying anti-rheumatic drugs; TNF, tumour necrosis factor.

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